Recent research has discovered the ubiquitous synthesis and use of nitric oxide (NO) throughout the biological systems of animals. For example, NO has been found to play a role in blood pressure regulation, blood clotting, neurotransmission, smooth muscle relaxation, and immune systems. For example, within the immune system, NO is believed both to inhibit key metabolic pathways, thereby inhibiting tumor growth, and to serve as an outright toxin that can be used to kill cells.
Furthermore, NO has been found to be a potent vasodilator within the bronchial circulation system of the lungs and is believed to play an important role in regulating pulmonary circulation. Nitric oxide is also believed to relax the muscles within lung airways, thereby regulating breathing.
Thus, it is believed that the insufficient production of NO within various biological functions results in deleterious effects as manifested in various immune deficiencies, asthma, bacterial infections, impotence, and high blood pressure, to name a few. From a pharmacological standpoint, the delivery of NO to the body may serve as a remedy for ailments caused by the insufficient production of NO within the body.
Nitric oxide, however, as it is used within the enumerable biological functions of animals, is highly controlled and regulated because excess amounts of NO can be hazardous to living animals. For example, the introduction of NO into the blood stream can cause the irreversible lowering of blood pressure, ultimately leading to death. Thus, the introduction of NO into the body is not the simple solution to the effects caused by insufficient NO production within the body.
There are known pharmaceutical compositions capable of delivering NO. Namely, Keeffer et al, U.S. Pat. No. 5,039,705, discloses pharmaceutical compositions of the formula

wherein R1 and R2 are independently chosen from straight chain and branched chain alkyl groups of 1 to 12 carbon atoms or benzyl, with the proviso that no branch occur on the alpha carbon of the alkyl groups, or R1 and R2 together with the nitrogen atom they are bonded to form a pyrrolidino, piperidino, piperazino or morpholino ring, M+x is a pharmaceutically acceptable cation, wherein x is the valence of the cation. Because this particular compound is a salt, the preferred method of administering this compound to animals is through injection into the bloodstream. It is also noteworthy that this particular compound is highly soluble in biological fluids thereby quickly releasing the NO which is loaded to the molecule.
Also, Keeffer et al., U.S. Pat. No. 5,366,997, discloses a similar pharmaceutical composition of the formula

wherein R1 and R2 are independently chosen from C1 to C12 straight chain alkyl, C1 to C12alkoxy or acyloxy substituted straight chain alkyl, C2 to C12 hydroxy or halo substituted straight chain alkyl, C3 to C12 branched chain alkyl, C3 to C12 hydroxy, halo, alkoxy, or acyloxy substituted branched chain alkyl, C3 to C12 straight olefinic and C3 to C12 branched chain olefinic which are unsubstituted or substituted with hydroxy, alkoxy, acyloxy, halo or benzyl. In another embodiment, R1 and R2 can also comprise various heterocyclic ring molecules as described therein.
It should be appreciated that the molecules as described by Keeffer at al are soluble within body fluids. Chemistry dictates as much, as does the disclosure of Keeffer et al as it is recommended to administer these drugs intravenously. It should further be appreciated that upon the intravenous introduction of these chemicals to a living animal, NO will be introduced throughout the body as the soluble compound disseminates throughout the body. As discussed above, unwarranted or overexposure of NO can have many harmful effects on living animals.
The importance of nitric oxide (NO) in biological repair mechanisms is well known even though the precise mechanism of its action has not been completely elucidated. Nitric oxide is known to inhibit the aggregation of platelets and to reduce smooth muscle proliferation, which is known to reduce restenosis. When delivered directly to a particular site, it has been shown to prevent or reduce inflammation at the site where medical personnel have introduced foreign objects or devices into the patient.
Researchers have sought various ways to deliver NO to damaged tissue and to tissues and organs at risk of injury. Nitric oxide can be delivered systemically, but such delivery can bring undesired side effects with it. Ideally, NO should be delivered in a controlled manner specifically to those tissues and organs that have been injured or are at risk of injury. Various compounds have been used to deliver NO therapeutically. Diazeniumdiolates (NONOates) exhibit the ability to release NO in the presence of a proton donor. Other classes of NO donors either require enzymatic activation to release therapeutic levels of nitric oxide, or they release both NO and undesired free radicals.
For purposes of this disclosure, those amine molecules that have been reacted with NO will be referred to as having NO loaded thereto. Heretofore in the art, those amine molecules having NO loaded thereto have been referred to as NONOates. Thus, the NO donor molecules of the present invention are NONOates.
The use of NONOates for the release of nitric oxide to specifically treat tissue that has been injured or is at risk of injury during sepsis or shock has been described in at least Saavedra et al., U.S. Pat. No. 5,814,656, the disclosure of which is incorporated herein by reference. Insoluble polymeric NONOates have also been generally described in Smith et al, U.S. Pat. No. 5,519,020, the disclosure of which is also incorporated herein by reference. These polymers were used to deliver NO to specific tissues, and results have shown that controlled release of NO to a specific site greatly reduced the inflammation and accelerates the healing process at that site. However, heretofore, these compositions have had to be delivered either by topical application or by coating onto the medical device. While such applications have been successful, the need continues to exist to provide a manner in which the NONOate compositions could be exposed to a greater surface area of the medical devices to which they are applied. The use of NONOates as coatings on implantable medical devices is also disclosed in Stemler et al., U.S. Pat. No. 5,770,645, the disclosure of which is also incorporated herein by reference.
In addition to the need set forth hereinabove, the process of coating some medical devices, particularly implantable devices, may have adverse effects on and alter the physical properties of the device. This can contribute to serious complications from the body's own defense to the medical device as foreign material.
The technique of electrostatic spinning, also known within the fiber forming industry as electrospinning, of liquids and/or solutions capable of forming fibers, is well known and has been described in a number of patents as well as in the general literature. The process of electrostatic spinning generally involves the introduction of a liquid into an electric field, so that the liquid is caused to produce fibers. These fibers are generally drawn to a cathode for collection. During the drawing of the liquid, the fibers harden and/or dry. This may be caused by cooling of the liquid, i.e., where the liquid is normally a solid at room temperature; by evaporation of a solvent, e.g., by dehydration (physically induced hardening); or by a curing mechanism (chemically induced hardening).
Previously known NONOates, however, are soluble in physiological mediums, and thus disseminate throughout the body once introduced therein. NONOates, which are insoluble in physiological mediums, upon introduction into the body, will not rapidly be distributed throughout the body allowing for the site specific delivery of NO, and are thus very desirable. Thus, there is a need in the art for a NO generating compound or compounds that are insoluble in physiological mediums. Physiological mediums will refer to those environments found within the bodies of animals, particularly humans, and include aqueous mediums.